Pain is a complex and poorly understood bodily response and a major health problem that often confers a low quality of life. In clinical practice, an “ideal” analgesic should: (a) reduce pain with high efficacy; (b) provide convenient dosing and predictable serum concentrations; and (c) exert minimal side effects and abuse liability. Current analgesics possess one or two of these properties, but none of them relieves pain completely and/or without side effects or addiction issues.
Opioids are the oldest and most prescribed analgesics, primarily as a first-line choice for acute and chronic surgical, cancer, and back pain. Opioids are divided into two primary classes: (a) “mu-active” drugs (e.g., morphine), which are selective for the mu-opioid receptor, and (b) “mixed agonist/antagonist” drugs (e.g., butorphanol, nalbuphine), which typically recognize mu- and kappa-opioid receptors. While opioids are effective in their primary indications, they elicit many limiting side effects, including constipation, respiratory and cardiovascular depression, nausea, urinary retention/diuresis, sedation, dysphoria, tolerance, and/or physical dependence, which seem virtually inseparable from their analgesic effects. Due to such problems, pain patients sometimes take less than the prescribed dosage and/or endure pain rather than suffer from side effects. Such problems also plague physicians, who must monitor patients closely, rotate different drugs to determine the most tolerable drug and dosage, and/or administer extra medicines to counteract side effects.
Morphinans are compounds based on the core chemical structure

Morphine, a widely used and powerful analgesic, is a common example of a morphinan. Morphine is an opioid that binds to opioid receptors in the central nervous system. However, the drug has serious side effects that present severe clinical problems, including drug dependence, suppression of respiration and suppression of smooth muscle movement. Alternative morphinan analogs have been studied and investigated in a search for compounds that shares the benefits of morphine with fewer negative side effects.
Due to the side effects and chemical dependency liability of currently available analgesics, there here nonetheless remains a need for additional opioid analgesics. Effective, non-addicting analgesics are particularly needed. The novel morphinan compounds of Formula I disclosed herein fulfill this need and provide additional advantages that are discussed in this disclosure.